Obesity contributes to hyperlipidemia and cardiovasular disease. Fructose consumption and obesity have both increased markedly during the past 2 decades. Compared with glucose, fructose is preferentially metabolized to lipid in the liver. Fructose consumption has been shown to induce hyperlipidemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, and hypertension (metabolic syndrome) in animal models. While there are some corroborative data from human studies, comprehensive mechanistic studies of the long-term effects of fructose consumption have not been conducted in humans. Our preliminary results from both short-term and long-term studies indicate that, compared to glucose, fructose consumption induces postprandial hypertriglyceridemia and increases plasma levels of atherogenic apoplipoprotein B (ApoB). In addition, fructose does not stimulate insulin secretion and leptin production, or suppress circulating levels of the orexigenic gastric hormone ghrelin. The effects of fructose on these hormones involved in body weight regulation suggest that consumption of high fructose diets may lead to increased energy intake, obesity, and insulin resistance, thereby exacerbating hyperlipidemia and predisposition to cardiovascular disease. The proposed studies will: 1) Investigate the mechanisms by which fructose consumption leads to increases of triglycerides and ApoB production using stable isotopes to assess de novo lipogenesis and ApoB kinetics. 2) Determine if subjects with components of the insulin resistance (metabolic) syndrome (existing hyperlipidemia and hyperinsulinemia) are more susceptible to the hyperlipidemic effects of fructose consumption. 3) Determine whether long-term fructose consumption also affects other lipid, endocrine and inflammatory mediators that would be expected to be atherogenic, including lipoprotein particle size, remnant lipoproteins, PAl-1, adiponectin, ASP, IL-6, and C-reactive protein. 4) Determine whether the lack of effects of fructose on endocrine signals regulating energy balance leads to increased appetite, energy intake, and body adiposity when fructose is consumed in conjunction with an ad libitum diet. These long-term (10 week) intervention studies will provide valuable information regarding the metabolic, endocrine, and atherogenic effects of fructose consumption in normal and hyperlipidemic, insulin resistant humans. The results are pertinent to the dietary control of cardiovascular disease, obesity, and other components of the metabolic syndrome.